Several mechanisms by which tumors escape host immune recognition and surveillance have been discovered. Tumor cells can actively evade immune recongnition by secreting immunosuppressive factors. Alternatively, tumor antigens are poorly recognized because they are non-mutated, weakly immunogenic tissue-specific differentiation antigens. Weak immunogenicity of these peptide antigens may be due to self-tolerance arising from deletion of autoreactive T cells or T cell hyporeactivity. New strategies for increasing the immunogenicity and therapeutic efficacy of tumor-derived antigens and the synthetic peptides corresponding to immunogenic epitopes with in these proteins have been developed and are the focus of this review. T cell responsiveness to a peptide epitope is affected both by its affinity for the presenting Major Histocompatibility Complex (MHC) molecule and the affinity of the MHC-peptide complex for the T cell receptor (TCR). Thus far, the most commonly attempted approach has been to increase MHC binding affinity of native peptides by introducing conservative substitutions at MHC-binding anchor positions. T lymphocytes have been shown to have no single ligand specificity, but rather can recongnize a set of structurally similar peptides. Synthetic peptides whose sequence is based on a wild type or native peptide, yet carry amino acid substitutions at various position along the chain are operationally defined as APL(altered peptide ligands). These APL can mediate a number of different outcomes in interacting with Tcells, ranging from inducing selective immunological functions (partial agonist) to completely turning off their functional capacity (antagonist). In addition to suboptimal ligands, TCR can also be triggered by superagonists, which are analogs that enhance T-cell stimulation and sometimes induce immunological functions not detected with the cognate ligand. Thus a promising approach to cancer immunotherapy is to design amino acid substituted MHC class I-restricted tumor peptide antigens that increase the stability of the MHC-peptide-TCR complex, enhance T-cell activation and anti-tumor responses. In this review we summarize recent developments in cancer immunotherapy based on APLs and point out future directions and applications for their use.
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